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W. H. SAWYER and M. MANNING

SUMMARY

The 4-threonine analogues of oxytocin and of mesotocin and isotocin were prepared by solid-phase synthesis. [4-Threonine]-oxytocin is about twice as active as oxytocin in rat uterus assays in vitro and in vivo and about three times as active in fowl vasodepressor assays. It is slightly more active than oxytocin in rat or rabbit milk-ejection assays. When infused intravenously into water-loaded rats it causes much less depression of diuresis than does an equal dose of oxytocin. [4-Threonine]-oxytocin has much less vasopressor activity than oxytocin. [4-Threonine]-mesotocin also shows enhanced oxytocin-like properties. Its oxytocic activity is equal to or greater than that of oxytocin and its fowl vasodepressor potency is about the same as that of [4-threonine]-oxytocin, 1500 u./mg. It also has less antidiuretic and vasopressor activities than mesotocin. Thus 4-threonine analogues, containing nothing but common l-amino acids, appear to have more of the specific oxytocin-like properties and less of the vasopressin-like properties than do oxytocin or mesotocin. Thus they may be considered improvements on the natural hormones. In this respect they are unique among the reported synthetic analogues of natural peptide hormones.

Substitution of 4-threonine in the weakly-active analogue [3-leucine]-oxytocin also increases its oxytocic and fowl vasodepressor activities. Thus a threonine in the 4-position appears to endow oxytocin-like peptides with greater specific activities than do the amino acids that occur naturally in this position, glutamine and serine. These observations may be of interest when considered (a) from an evolutionary viewpoint, (b) in attempting to interpret relations between molecular structures and biological activities, and (c) as describing peptides with more of the desired properties of oxytocin and less of the undesired properties which might have therapeutic advantages over the natural hormone.

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J. Kruisbrink, J. J. van Heerikhuize and G. J. Boer

ABSTRACT

The cerebrospinal fluid level of arginine vasopressin (AVP) or vasoactive intestinal polypeptide (VIP) was enhanced chronically by implantation of a device for controlled drug delivery in the lateral ventricle of the rat. Urine production, water consumption, urine osmolality as well as urinary AVP excretion were then measured for a period of 26 days. During this period the rats were studied under normal hydration and under conditions of osmotic stress induced by water deprivation (2 days) and the drinking of 2% (w/v) NaCl (6 days), in order to see whether the capacity of central systems to react adequately to osmotic stimuli was affected by high central peptide levels.

Immediately after the central AVP treatment was started, a temporary increase was found in urinary AVP levels which was not accompanied by a change in any of the other parameters but which decreased again to control levels within 10 days. After this burst of AVP excretion, AVP-treated rats showed a tendency during periods of normal hydration for a lower urine osmolality, combined with a higher water intake and urine production without changes in urinary AVP excretion. Since there was no clear-cut correlation between urinary AVP excretion and body water turnover, this could still indicate a slowly acquired and slight inhibition of pituitary AVP release by long-term centrally administered AVP. However, the capacity of these rats to respond to osmotic stimuli was not different from the controls.

In the VIP-treated rats a slight but significant reduction in urine production was found in all three periods of normal hydration. During the osmotic stress induced by the drinking of 2% NaCl the VIP-treated rats showed a lower increase in urine production and fluid intake and a lower decrease in urine osmolality when compared with the response of the control rats. This has tentatively been interpreted as a potentiation by VIP of the activation of pituitary AVP release under these conditions.

J. Endocr. (1988) 117, 207–214

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R Vasilatos-Younken, Y Zhou, X Wang, JP McMurtry, RW Rosebrough, E Decuypere, N Buys, VM Darras, S Van Der Geyten and F Tomas

In contrast to most vertebrates, GH reportedly has no effect upon somatic growth of the chicken. However, previous studies employed only one to two dosages of the hormone, and limited evidence exists of a hyperthyroid response that may confound its anabolic potential. This study evaluated the effects of 0, 10, 50, 100 and 200 microgram/kg body weight per day chicken GH (cGH) (0-200 GH) infused i.v. for 7 days in a pulsatile pattern to immature, growing broiler chickens (9-10 birds/dosage). Comprehensive profiles of thyroid hormone metabolism and measures of somatic growth were obtained. Overall (average) body weight gain was reduced 25% by GH, with a curvilinear, dose-dependent decrease in skeletal (breast) muscle mass that was maximal (12%) at 100 GH. This profile mirrored GH dose-dependent decreases in hepatic type III deiodinase (DIII) activity and increases in plasma tri-iodothyronine (T(3)), with bot! h also maximal (74 and 108% respectively) at 100 GH. No effect on type I deiodinase was observed. At the maximally effective dosage, hepatic DIII gene expression was reduced 44% versus controls. Despite dose-dependent, fold-increases in hepatic IGF-I protein content, circulating IGF-I was not altered with GH infusion, suggesting impairment of hepatic IGF-I release. Significant, GH dose-dependent increases in plasma non-esterified fatty acid and glucose, and overall decreases in triacylglycerides were also observed. At 200 GH, feed intake was significantly reduced (19%; P<0.05) versus controls; however, additional control birds pair-fed to this level did not exhibit any responses observed for GH-treated birds. The results of this study support a pathway by which GH impacts on thyroid hormone metabolism beginning at a pretranslational level, with reduced hepatic DIII gene expression, translating to reduced protein (enzyme) ex! pression, and reflected in a reduced level of peripheral T(3)-degrading activity. This contributes to decreased conversion of T(3) to its inactive form, thereby elevating circulating T(3) levels. The hyper-T(3) state leads to reduced net skeletal muscle deposition, and may impair release of GH-enhanced, hepatic IGF-I. In conclusion, GH has significant biological effects in the chicken, but profound metabolic actions predominate that may confound positive, IGF-I-mediated skeletal muscle growth.

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Melissa F Jackson, Dung Luong, Dor Dor Vang, Dilip K Garikipati, James B Stanton, O Lynne Nelson and Buel D Rodgers

beneficial effects on obesity-related disorders, on preventing frailty, and on mitigating cardiovascular disease ( Winett et al . 2009 ). Thus, a better understanding of sarcopenia or mechanisms to enhance skeletal muscle mass could help to develop novel

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Lisa M Arendt, Lindsay C Evans, Debra E Rugowski, Maria Jose Garcia-Barchino, Hallgeir Rui and Linda A Schuler

estrogenic signals in a variety of experimental systems: it increases ER expression ( Edery et al . 1985 , Frasor & Gibori 2003 , Gutzman et al . 2004 a ), and cooperatively activates the AP-1 transcriptional enhancer ( Gutzman et al . 2005 ). These

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Isabel R Orriss, Dilek Guneri, Mark O R Hajjawi, Kristy Shaw, Jessal J Patel and Timothy R Arnett

-thioUTP (≥0.1 µM) dose-dependently increased extracellular ATP levels by up to 50% (F, G, H) but had no effect in P2Y 2 R −/− osteoclasts. Long-term treatment (7 days) with (I) UTP and (J) 2-thioUTP treatment enhanced ATP release by up to 70% and 65

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Sarit Ben-Shmuel, Eyal J Scheinman, Rola Rashed, Zila Shen Orr, Emily J Gallagher, Derek LeRoith and Ran Rostoker

triglycerides levels in serum, were shown to have enhanced mammary tumor growth. Cholesterol-induced activation of the PI3K/Akt signaling pathway in tumor cells was suggested as the molecular mechanism linking hypercholesterolemia and tumor growth ( Alikhani et

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C H Knight

Abstract

The milk yield-enhancing effect of oxytocin administered either before or after milking was examined using a within-animal model. Eight cows in mid-lactation were changed from normal twice daily milking to a split-milking design, whereby half of the udder was milked at 0500 and 1500 h (control half; normal milking times), and the other half at 0800 and 1800 h (test half). This continued for 3 weeks. During the second week, oxytocin was administered as an i.m. injection immediately before the 0800 and 1800 h milkings. The test half was thus milked immediately after oxytocin administration, whilst the control half was milked 3 h before oxytocin. Milk yield decreased slightly on the adoption of split-milking. The decrease did not differ between udder halves and was not, therefore, due to inadequate milk-ejection in the test half compared with the control. During the week of oxytocin treatment, the yield decreased further in the control half but increased in the test half; consequently, the yield from the test half was significantly greater than that from the control half (P<0·05). The ratio of change in the test half relative to that in the control half was 1·12, significantly different from unity (P=0·002). Analysis of variance demonstrated a significant (P<0·001) interaction between udder half and oxytocin treatment, confirming that the effect of oxytocin was restricted to the test half, treated immediately before milking. This supports the established view that oxytocin acts by enhancing the milk-ejection reflex, and refutes a recent claim that the hormone has a direct stimulatory action on mammary metabolism.

Journal of Endocrinology (1994) 142, 471–473

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H-M Shieh, R T Bass, B S Wang, M J Corbett and B L Buckwalter

Abstract

In this study, the epitope of a murine PS-7·6 monoclonal antibody (mAb) which was raised against the recombinant porcine GH (pGH) and subsequently shown to enhance the growth-promoting activity of pGH in a hypophysectomized rat model, was mapped by the limited tryptic digestion of pGH. A pGH fragment corresponding to amino acid residues 70–95 was separated by reverse-phase HPLC and also immunoprecipitated by PS-7·6 mAb. This fragment was found in an RIA to compete with radiolabelled pGH for the binding of PS-7·6 mAb in a dose-dependent fashion. Several peptides covering this potential epitope region of pGH(70–95) were synthesized and assayed by competitive RIA. The results suggested that pGH(75–90) was the optimal sequence recognized by PS-7·6 mAb. Sequential alanine substitution of each residue of pGH(75–90) revealed that the side chains of Leu76, Ile83 and Leu87 were critical for binding to PS-7·6 mAb. Other residues could be replaced by alanine without substantially altering the binding affinity. The region of amino acids 75–95 comprises the C-terminal end of the second helix of pGH and the repeating pattern of i and i+3 (i+7) of the critical amino acids appears consistent with PS-7·6 mAb binding to the hydrophobic side of the helix. The sequence and the helical structure of the epitope of PS-7·6 mAb provide the basis for designing the effective peptide vaccines to enhance the growth performance of animals.

Journal of Endocrinology (1995) 145, 169–174

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R A Hill, H C Flick-Smith, S Dye and J M Pell

Abstract

We have previously demonstrated that a specific antiIGF-I antibody will enhance the growth-promoting activity of IGF-I in vivo (Stewart et al. 1993). Since the antibody had a modest affinity for IGF-I we suggested that the antiserum might protect IGF-I from degradation whilst maintaining it in a bioavailable form. The aim of this investigation was to test that hypothesis by determining the plasma clearance and tissue distribution of tracer IGF-I in the presence of the enhancing anti-IGF-I immunoglobulin (anti-IGF-I Ig) or non-immune immunoglobulin (NI Ig).

Dwarf rats were treated with saline, NI Ig or anti-IGF-I Ig for 4 days. On day 4, 125I-IGF-I (1·6 × 107 c.p.m.) was injected into the jugular vein and blood sampled over the next 330 min when the rats were killed; samples of liver, kidney and skeletal muscle were quickly dissected out. Mean plasma trichloroacetic acid (TCA)-precipitable 125I-IGF-I was always significantly greater (P<0·001 for each time point) from anti-IGF-I Ig rats versus the NI Ig or saline groups (which exhibited practically identical decay curves), implying increased binding capacity for IGF-I in the anti-IGF-I Ig rats. Pharmacokinetic parameters were calculated by resolution of the decay curves using a two-phase model. The total clearance rate of 125I-IGF-I was significantly decreased (P<0·001) by almost twofold in the anti-IGF-I versus the two control groups, consistent with the increased binding capacity in the anti-IGF Ig rats. The half-lives of the faster-decaying phase were not significantly different between treatment groups but, surprisingly, that for the slower-decaying phase was significantly decreased (P<0·001) in the anti-IGF-I Ig rats versus the two control groups; this may reflect the low affinity of the anti-IGF-I Ig for IGF-I and its enhancing properties. The degradation of 125I-IGF-I was significantly decreased in animals receiving the anti-IGF-I Ig. In support of this, kidney TCA-precipitable radioactivity (c.p.m.) was sevenfold less (P<0·001) in the anti-IGF-I Ig groups versus the controls, indicative of reduced excretion. Liver TCAprecipitable radioactivity was increased (P<0·001) in the anti-IGF-I Ig rats, probably due to reticuloendothelial clearance of non-self antibodies; skeletal muscle TCAprecipitable radioactivity tended to increase in the antiIGF-I Ig group versus the controls which might indicate increased targeting of IGF-I to muscle. Size exclusion chromatography of plasma 15 and 120 min after administration of 125I-IGF-I demonstrated a broad peak of radioactivity with a molecular mass of 150–300 kDa in the anti-IGF-I Ig-treated rats, which was responsible for more than 90% of the eluted radioactivity. This suggests that: (1) 125I-IGF-I was bound to the anti-IGF-I Ig and might also be able to associate with IGFBPs or (2) the polyclonal antibody might recognise more than one antigenic site on IGF-1.

These data indicate that the anti-IGF-I Ig was protecting IGF-I from degradation, leading to a larger plasma pool of IGF-I but that IGF-I could be transferred readily from the plasma pool to tissues. We suggest that administration of IGF-I in conjunction with a binding molecule similar to the antibody described here could provide the basis for effective IGF-I treatment strategy.

Journal of Endocrinology (1997) 152, 123–130